1. Management of Chronic Pulmonary Aspergillosis
Chris Kosmidis, MD, PhD
Consultant in Infectious Diseases
Manchester University NHS Foundation Trust

2. Intended Learning Outcomes
To be aware of the medical management of chronic pulmonary aspergillosis
To understand the role and indications of intravenous antifungals in the management of CPA
To be aware of the prognosis and predictors of poor outcomes in CPA

3. Principles of CPA management
Oral azole therapy is key
Therapy is long-term as relapse is common off therapy
Itraconazole, voriconazole and posaconazole all effective
Major drug interactions and common, serious side effects – drug level monitoring recommended
IV Amphotericin B or echinocandins useful for failure of oral azole therapy
Interferon-gamma supplementation helpful in some cases
Some patients appear not to progress, but should to be kept under observation, as progression may be subclinical
Minimise other causes of lung infection with immunisation and antibiotics
Withdraw or minimise immunosuppressive drugs wherever possible, including inhaled steroids
Monitor for azole resistance

4. Management of CPA CPA entity Initial therapy Duration
Alternative therapy
Cautions
Simple aspergilloma
Surgical resection ..
None
Sufficient respiratory reserve, relapse is possible
Aspergillus nodule
None, if asymptomatic
Azole therapy, if progressive
If multiple, continued imaging and
possibly repeat biopsy if progressive
Chronic cavitary and fibrosing CPA
Itraconazole or voriconazole
>6 months , typically long-term
Posaconazole, Isavuconazole, liposomal amphotericin B, echinocandins
Drug interactions, especially
rifampicin; long-term toxicity include
peripheral neuropathy and skin
photosensitivity (voriconazole)
Denning & Chakrabarti Lancet Infect Dis. 2017: S (17)

5. Objectives of antifungal therapy
Very ill patients:
Save their lives with (usually) IV and then oral therapy
Quite ill patients:
Improve quality of life by minimising symptoms
Prevent further haemoptysis (coughing blood)
Stop progression of scarring in the lung
Prevent the emergence of antifungal resistance
Avoid antifungal toxicity
Patients with few symptoms or asymptomatic
Regression of Aspergilloma on treatment
September , 2013
Aspergilloma
September , 2016
No Aspergilloma

6. CPA management framework
Itraconazole
Voriconazole
Posaconazole
Isavuconazole
IV Amphoterin B or echinocandins
Key challenges
Antifungal resistance
Adverse events
Drug-drug interactions

7. Response rate to antifungal therapy
Itraconazole: 76.5% [6 mo]1
Voriconazole: 64% (3 mo )2, 32 % (6 mo)3
Posaconazole: 61% [6mo] vs 46% [12 mo]4
1Agarwal et al. Mycoses Sep; 56(5):559-70
2Jain et al. J Infect May; 52(5):e133-7.
3Cadranel et al . Eur J Clin Microbiol Infect Dis Nov;31(11):
4Felton et al. Clin Infect Dis Dec 15;51(12):

8. Response rate to antifungal therapy
Micafungin and Voriconazole for CPA
Response rate at 2-12 weeks
Caspofungin: 47%
Micafungin: 42%
Micafungin and Voriconazole for CPA
Response rate at 2 weeks
Micafungin: 68%
Voriconazole: 59%
Response rate at 4 weeks
Micafungin: 60%
Voriconazole: 53%
Kohno et al. J. Infect. 2010;61:410-8.
Kohno et al. Eur J Clin Microbiol Infect Dis. 2013;32:

9. Itraconazole randomised clinical trial
Oral itraconazole
6 mo mo
35%
41%
Stable
Improved
Standard care
6 mo mo
23% 7%
29%
64%
71%
53%
21%
24%
Deterioration
30% relapse off therapy in 6 months
Natural history with no therapy over 12 months
Agarwal et al 2013: Mycoses Sep;56(5): doi: /myc Epub 2013 Mar 18
31 patients: Randomised to Itraconazole (n=17) or no antifungal [supportive treatment only] (standard of care)(n=14): Overall response 76.5% vs. 35.7% (p=0.02)
Response measure : Clinical or radiological , and overall
Outcome:
Clinical response was classified as improved, stable or worsened based on assessment of patient's sense of well-being, gain in weight, improvement in cough and exercise capacity, decrease in the number, and frequency and quantity of haemoptysis.
Radiological response was considered present if there was decrease in the size/number of the fungal balls, attenuation of the paracavitary infiltrates or pleural fibrosis. The response was assessed objectively by measuring the longest diameter of various lesions and a 50% reduction was taken as criteria for improvement.
Overall response was classified as: (a) improved: improved or stable clinical response and radiologically improved or stable disease; and (b) failed: worsening of symptoms or radiological progression. All outcomes were assessed at the end of 6 months of therapy.
Follow up
Patients were followed up for at least 6 months following completion of treatment.
Agarwal R, et al, Mycoses :

10. Intravenous antifungals for CPA
Amphotericin B or echinocandins
Short-term course (2-4 weeks)
Useful initial therapy in severe disease
Symptomatic benefit may persist for weeks / months after completing course
3 – 4 courses per year can be given as a long – term management option
Indications:
Progressive disease
Treatment failure on oral azoles
Intolerance to triazoles
Pan-azole resistance
Infection control strategy (IV induction followed by an oral maintenance therapy )
Kohno et al J Infect 2010; 61: 410–418.

11. Outcome (survival) of treated CPA
1 Year
86%
5 Years
62%
10 Years
47%
Lowes et al Eur Respir J. 2017;49:pii:

12. Recurrence (relapse) of CPA
Relapse of CPA symptoms are common following discontinuation of long-term maintenance therapy.
Relapse can be:-
Clinical
Worsening of clinical manifestations
Radiological
Enlargement of fungal balls or pre-existing cavities
Serological
Rising Aspergillus IgG titres
Microbiological
Strong PCR signals, culture positivity

13. Recurrence of CPA Predictors After medical treatment
41% (India) Agarwal et al. 2013
36% (Japan) Koyama et al 2014
17% (France) Cadranel et al 2012
11% (Italy) Cucchetto et al 2015
Post-surgical relapse
26% (UK) Farid et al 2013
3.9% (Seoul, S. Korea) Lee et al 2009
Predictors
Younger age
Bilateral or multilobar CPA disease
Longer antifungal treatment duration
Agarwal et al. Mycoses. 2013;56:559–70.
Koyama et al. J Infect Chemother. 2014;20:375–9
Cadranel et al. Eur J Clin Microbiol Infect Dis. 2012;31:3231–9
Cucchetto et al. Infection. 2015;43:277–86.
Farid et al J Cardiothorac Surg .2013;8:180.
Lee et al. J Thorac Cardiovasc Surg ;138:820–5

14. Prognostic factors Increased mortality is associated with:-
Low body mass index
NTM co-infection
Underlying COPD
Higher age
Lower albumin
Lower activity score in the St. George's Quality of Life score
Bilateral aspergilloma >>aspergilloma
Lowes et al Eur Respir J. 2017;49. pii:

15. Summary
Long-term oral triazole therapy is the mainstay for the management of chronic pulmonary aspergillosis
Itraconazole, voriconazole and posaconazole are all effective
IV Amphotericin B or echinocandins useful after failure of oral azole therapy
Relapse of CPA symptoms are common following discontinuation of long-term maintenance therapy